Processes for the production of new carbohydrate compounds



Sept. 2, 1952 K. M. GAVER ETAL PROCESSES FOR THE PRODUCTION OF NEWCARBOHYDRATE COMPOUNDS Filed Aug. 51, 1946 5 Sheets-Sheet 2 Iglu/zic ,haJ0 zuffm| Fcacizon fofrod'uce .Z-Mnowyanzc,

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' INVENTOR` KENNETH M. GAVL'R L'RI V. TIl'JZE/V EJTHER P- d'IRE N www,M, Tcir Tfaf/ffv Sept. 2, 1952 K. M. GAVER ErAL 2,609,370

PROCESSES FOR THE PRODUCTION OE NEW OARBOHYORATE COMPOUNDS Filed Aug.31, 194e 5 SheetE-Sheet 3 l rgcmzc H all' de Re ac tion to produce @-Mona Metallic R I X organi c 2Mono aI'aZ'tqrc/rae 'a t Org alge Hal' deReac fio/1 to ,ora duce 2,6-Dz'orgdnig Metallic R X .'i-MqnaalkalSalC/Iafe fait Reaczgn fa gro duce Z, 3, 'ubsu fion to ,oro duce Trlorga/uc ,Starch aie 2, 6- z'organ g3-Ivre tall zc BY FWN A;

Sept 2. 1952 K. Ml GAvl-:R ET AL 2,609,370

kPROCESSES FOR THE: PRODUCTION OF NEW CARBOHYDRATE COMPOUNDS A FiledAug. 31, 1946 5 Sheets-Sheet 4 @I u IHaHya'ox/e in Non-Hqueous ,Solve/vfl I Hydralysl, E Lc.

IN V EN TORS Sept Z, 1952 K. M. GAVER Erm.

PROCESSES FOR THE PRODUCTION OF NEW CARBOHYDRATE COMPOUNDS Filed Aug.51, 1946 5 sheets-sheet 5 Replcemenf of 14n on o ups ofMz/l'fl'v alenfBerl vatlves Glucosl'dl'o Hydro/gsi: of Salchafe fo [grade/ce 6'"MonoorganlQoC-a/g/ G/uc'oscde Fig. 5.

[o produce 6 Monooryanlc Glucose E fflergfg'cafg'on EsferlfwafgonCondensq lon egradaon, efe.

KE/YIYEI'HM. GHI/lll PERI( '1I TIES'ZE/V 1557/151; P. .LHSURE PatentedSept. 2,

VCT;

UNITED STATES PATENT oFFIcE PROCESSES FOR THE PRODUCTION OE NEWCARBOHYDRATE COMPOUNDS Kenneth M. Gaver and Esther P. Lasure, Columbus,Ohio, and Derk V. Tieszen, Delmar, N. Y., assignors to Ohio StateUniversity Research Foundation, Columbus, Ohio, a corporation of OhioApplication August 31, 1946, seriai No. 694,328

The inventions disclosed in this application relate to new compositionsof matter or compounds and to new processes for the formation of a largenumber of such' new, compounds which have been heretofore unknown. Theprocesses described herein illustrating our invention are especiallydesigned to produce new products from starch and ordinarily include asone of the steps the hydrolysis of an intermediate compound to produce aglucoside, a glucose, or similar compound. l

In carrying out preferred embodiments of our process, we produce asintermediate products certain new compounds which we have discovered andsynthesized by our processes; these intermediate products in the natureof alcoholates of starch. To designate these compounds, we have coinedthe word starchate which we define as follows: "Starchate V'means and isused in this specification and in the claims hereof in the sense of acompound composed of an unde termine-d number of polymerizedgluco-pyranose units wherein one or more metallic atoms or inorganic ororganic radicals are substituted for the hydrogen atoms of one or moreof the several hydroxyl groups of the starch unit so as to form apolymerized compound which in fact is (or is at least analogous to) analcoholate of starch.

Prior to our inventions disclosed herein, a certain process had beendiscovered for the substitution of alkaline metals in the starchmolecule to form a starchate which we will refer to hereinafter as theammonia process and the ammonia process starchate. As demonstrated inco-pending application Serial No. 357,995, now abandoned, and inthecontinuation thereof Serial No. 707,318, now Patent No. 2,518,135, andas demonstrated hereafter in this applicationsuch prior art processeslproduce starchates which differ essentially from many of the starchatesdisclosed as intermediate products in this application. Also, inco-pending application Serial No. 357,995, now abandoned, and in thecontinuation thereof Serial No. 707,318, now Patent No. 2,518,135, thereisv disclosed the formation of a monosodium starchate and othermonoalkali starchates and monometallic ,and monoorganic derivativesthereof, but as was demonstrated in said prior applications and as willbe demonstrated hereafter herein such starchates also differ from theammonia process starchates" and from the polysubstituted starchatesdescribed herein.

Also, according to prior art methods, mono an .polysubstituted productsof cellulose and of sirnple sugars had been prepared, as for example, asdescribed in Scherer and Hussey, Journal of American Chemical Society,53: 2344 (A1931) Schorigin et al., Berichte 69: 1713 (1936) Peterson andBarry, U. S. Patent 2,157,083, 1939; unknown British Patent 463,056(1937); Muskat, Journal of American Chemical Society, 56: 693 (1934) andMuskat, Journal of American Chemical Society, 56: 2449 (1934).A Aswillbe demonstrated hereafter in this application, thesesubstitutedproducts of cellulose and of sugars are diierent from the productsproduced by our improved process. Referring again to the prior artprocess designated above as the ammonia process, it may be noted thatSchmid-et al., (Chemical Abstracts 20: 744 (1926) and Chem. Cent. 2:1761 (1928)) .produced a monoalkyl derivative of starch by treating thestarch with an alkali metal in liquid ammonia. Either as a final productor as an intermediate product these investigators Vobtained amonoalkalicompound in which it was concluded that the reaction occurredon the six position carbon in theglucose unit of theA starch molecule.Other investigators obtained sodium hydroxide adsorption compounds bydissolving starch in aqueous alkali followed by alcohol precipitation orby treating starch with alkali metal alcoholates. These compounds,however, were not starchates in that the alkali metal did not enter intothe starch molecule.

Likewise, if glycogen, inulin, etc. are treated in liquid ammonia withan alkali metal, a monoalkali derivative as formed which is similar tothe ammonia process starchates referred in the last paragraph Thismonoalkali derivative differs essentially from the monoalkali derivativeformed in the process described in application Serial No. 357,995 andthe continuation thereof in that the alkali metal in such ammoniaprocess starchates is attached to the No. 6 carbonatom whereas in themonoalkali -st archate described in -such prior application anddescribedherein in connection with many of the processes of our presentinventions is one in which the alkali metalv is attached to the No. 2carbon atom.

Heretofore as statedjabove, it has been possible Vby known processes tef orm compounds in which 2SogwEST AVAILABLEQOPY thesesubstituted groupsmight be placed nor has it been possible to form compounds in whichselected predetermined groups are substituted on the various hydroxylcarbon atoms nor to form compounds which have one group substituted onone carbon atom, a second group on a second carbon=atom and a thirdgroup on a third carbon atom. We can, by our new processes, form suchcompounds.

One of the objects of our invention` is the. provision of new and usefulprocesses of forming new and useful carbohydrates from starch.

A further object of our inventionV is the provision of new and usefulprocesses for forming various new products from starch.

A further object of our invention is the provision of new and usefulprocesses for forming various new and old glucoses and'. gl cosides.,

A further object of our invention is the provision of a new and usefulprocess of forming polysubstituted products from starch.

A'further object of our invention is the provision of new and usefulproducts formed from starch. l

Further objects and features of' our invention will be apparent from areading of the subjoined specifica-tion and claims when considered inconnection with the'accompanying drawings showing severalexemplaryprocesses illustrating certain embodiments of our inventions.

In the drawings:

Fig. 1 is a diagram illustrating a process of forming monoalkalistarchates, monoorganic starchates, starchates having. one or moreorganic radicals and an alkali group substituted on the lucts and alsoillustrating alternative steps by which monoorganic glucoses andglucosides and their derivatives; and nonalkali monometallic starchatesand mixed organic and metallic starchates and lderivatives thereof mayalso he 1 formed;

Fig. 3 is a similar diagram illustrating alternative similar processesfor producing the same and similar products, the first step of whichcomprises the processv of making ammonia process starchates;

Fig. 4 is a similar diagram illustrating alternativev processes forproducing similar products and disclosing among other new processes, newprocesses of producing mono and diorganc glucoses and glucoside's; and

Fig. 5 is a similar diagram illustrating the process of producingS-monoorganic glucoses and 6- rnonoorganic a-glucoside's and derivativesthereof.

v-In co-pending application Serial No. 357,995 and in the continuationsthereof, there are disclosed inventions relating to monometallicstarchates (bothalkali and nonalkali), to monoorganic l starchates, andto methods for their preparation. -In other (zo-pending applications wewill disclose polyalkali metal starchates,' polymetallic starchates(nonalkali) and mono and poly organic starchates (sometimes calledstarch ethers) and we reserve for-claiming in such co-pendingapplications the inventions relating to such processes and products. Theclaims of this application will be directed to the combination processesfor producing hydrolysis products of the various starchates produced byour improved processes and to the products produced therebyv Thesehydrolysis products naturally fall largely into the classes of glucoscsand glucosides. As will subsequently be demonstrated herein, the numberof these new glucose and glucoside products almost staggers theimagination. Most of these thousands of products have never heretoforebeen produced either naturally or synthetically.

K In', co-pending application Serial No. 357,995

and in the continuation thereof. there are disclosed inventions relatingto monoalkali metal starchates.. methods for their preparation, andderivatives thereof. The inventions so disclosed are based upon thediscovery that when starch is reacted with alcohol soluble hydroxides(such as the hydroxides of lithium, sodium, potassium, rubidium andcaesium) under certain conditions there is produced a metallic starchatewherein the alkali metal is attached through an oxygen atom to a carbonatom in the complex-glucopyranose residue (the structure commonlyconsidered' as the building unit of starch).

The starchate product formed lis a gluco-pyranose compound. Thestructural formula of the unit forming the building unit of the complexstarchate may be illustrated as follows wherein MA represents an alkalimetal:

I HO CHzCH(CH-)(CHOH)(CHOM) CHO This product We will designatehereinafter in this application as a 2-monoa1kali starchate. It wasdiscovered that when such 2-monoalkali starchate is dissolved in vwaterLa limpid solution results which may be neutralized and a starch productrecovered by precipitation with alcohol. This may be filtered, washed,dried, and ground. This product is entirely 'dierent from the originalstarch in that it is watersoluble. yielding a filterable, nonreducing,'faintly cloudy solution called starch hydrol. 'Howeven a solution ofstarch in an aqueous sodium hydroxide of identical concentration resultsina gel which when treated in identical manner yields a rubbery, waterinsoluble product resembling somewhat the original starch. If, however,the gel resulting from solution of the starch in aqueous sodiumhydroxide is allowed to stand at room temperature for a period of two ormore months time, a thin limpid solution results which is similar inproperties to the solution resulting from dissolving of 2-monoalkalistarchate in water. Heating of the alkaline solutic-n causes the wellknown alkaline degradation.

It has been known commonly heretofore that starch may be modified bytreatment with aqueous solutions oralkalies, alkaline salts, alkalineearth hydroxideafand other hydroxides to produce starch products whereina certain amount 'of the alkali, alkaline salts, alkaline earthhydroxide or other hydroxides is absorbed on the oxygen bridges withinthe building units I(i. e. on the 1,5-pyranose ringl" replacing thecoordinated water in anequimolecular proportion. It has long1 been'known ythat water as such was-a natural constituent of the starchmolecule and thermal decomposition data indicates that this water ispresent as coordinated water. It is generally acceptedjthat thiscoordinated water is positioned 'on the oxygen bridgeof the 1,5-pyranosering. Treatment in aqueous media with various metallic hydroxides isconducive to ion exchange whereby the metallic hydroxide replaces thewater of coordination. Various coordinated compounds have been reportedas having compositions represented by the following formulae: l

Similar compounds of beryllium, calcium, strontium, magnesium, zinc,laluminum, copper, iron and lead either aloneor in combination with othermetals have been reported. The inability of the various investigators tomake these compounds undergo the Williamson ether reaction is proof oftheir coordinated nature whereas our 2-monoalkali metal starchatesreadily undergo the Williamson ether reaction.

Obviously, in all these cases, the products formed in the abovementioned prior art processes were not compounds in the strictest sensebut rather coordinated complexes of poorly delned nature. The disclosureof the inventions claimed and described in said co-pending applicationsand herein show that Where starch is reacted according to our newprocesses and preferably by refluxing with an alcoholic solution ofalkali hydroxide (i. e. one containing 8 to 14% NaOH or its equivalent)for a sui'lcient time and under controlled conditions, an alkali metalstarchate compound (2-monoalkali metal starohate) is formed, whichcontains. 15.5 to 16.5% Na-OH or .its equivalent in the case of cerealstarches (e. g. rice) and from 19.3 to 19.8% NaOH or its equivalent inthe case of root starches (e. g. potato).

Investigation of the 2-monoalkali metal starchate (when tested bytitration and chemical reactions) deiinitely proves that the'starchderivative formed is not an addition or coordinated compound but is atrue alcoholate of starch. This is further borne out in that the2-monoalkali, metal starchates (particularly the sodium or potassiumstarchates) produced have been found to be adapted as disclosed hereinfor'use as starting compounds in making other metallic derivatives,ethers, esters, and other typical compounds using non-aqueous reactionmedium.

One of the most outstanding characteristics of the z-monosodiumstarchate made vaccording to the inventions being considered is that itpossesses a very low viscosity as compared with a simple solution ofstarch in sodium hydroxide. The products formed by the mere addition ofsodium hydroxide to starch do not show this low viscosity. Further it isfound that the surface tension of water is lower when a 2-monosodiumstarchate product is introduced. The iodine coloration also changes fromblue to red upon the formation ofsuch 2-monosodium starchate. Aqueoussolution of such 2-monosodium starchate having increased quantities ofcombined sodium hydroxide are lterable to an extent which is unexpected..This is in direct contrast to conventional solutions cf starch andalkali.

In preparing the 2-monoalkali starchates referred to above, We haveinvestigated the effect of the following factors on the reaction.

Temperatures D l Any temperature from 80 C. up to 115 C. in an 'open orclosed system, which permits the volatilization of the water producedin-the reaction produces Z-monosodium starchate. -If the system isclosed so that the water evolved in the reaction is retained in thereaction mixture, then the reac- BEST AVAILABLCOPY tion will yield2-monosodiumstarchate at any reasonable .temperature above'80" C., i. e.up to the dextrinization temperature (unknown in nonaqueous solvents butperhaps to 200 C. or higher) Somewhere above 115 C., in an open system,other reactions occur and the product is no longer 2-monosodiumstarchate. Under strongly dehydrating conditions, e. g. withalcoholates, this reaction can be driven to completion at temperatureslower than 80 C.

Pressure Apparently there is but very, very slight volume changesoccurring in this reaction. Pressures up to lbs. have been used with noeiiect on the course of the reaction or upon the product produced by thereaction. It is very probable that any practical pressure may be usedprovided the temperature and other requirements are not violated.

Time of reaction The time of reaction varies with the solvent chosen.With ethyl alcohol any time beyond two hours does not alter the courseof the reaction nor the character of the product.. With butanol, thereaction is complete by the time the butanol (technical grade) reachesthe boiling point of 115 C. A generalization may be made in that thereaction'is completed within two hours at 81 C. or instantaneously at115 C. or higher regardless of the-nature of the solvent. Anytemperature between 80 C. and -.115 -C. would require a proportionatereaction time (e. g. at C. the time required is about 75 min. and at C.the time required is about 15 min., etc.).

Alkali concentration t has been repeatedly demonstrated that thereaction is independent of alkali concentration and the same product isalways obtained provided there is suicient alkali present to satisfy therequirements of the product. At the lower temperature range, i. e. 80C., it is advisable to use an excess of alkali in order to complete thereaction in the two hour period. At the higher temperature range, i. e.C., or higher only an amount of alkali approaching stoichiometricequivalent is necessary. The mother liouor from the latter reactionalways shows a faint alkalinity approximating 0.04 N. This alkalinityapparently arises from the protein-alkali interaction product extractedIrom the starch. The

protein is known to be extracted from the starch and appears in themother liquor.

Nature of the alkali Of the alkalies vonly ammonia failed to react.Sodium and potassium hydroxide, sodium methylate, sodium ethylate,sodium propylate and sodium butylate all yield chemically similarproducts. Any caustic alkali or alkaline reacting material having asionization constant of 2x10-5 or greater will react provided thatit ismore than very slightly soluble in the chosen reaction media and-alsoprovidedthat the molecular size of the reacting molecule is not toolarge to locate itself in position to react with the starch.

Nature of the'carbohydrate Similar reaction products were prepared usingwaxy rice, yucca, sago, arrowroot, sweet potato, potato, corn, wheat,tapioca and amioca starches; a series of thin boiling starches; wheat,potato, tapioca and corn dextrins; dextron; cotton;

BEST AVAILABLE COPY linen.; Sucrcee.;cellulari-alliccsiileif11ste;essie? cellulose: and infelici,

Reducing eugersreacc. under. simile-r ceediiiene te. produce ill definedSirens Whchenelyze ic, be monosodium derivatives but which were notbteiried in euicieet. purity te. be characterized- Iliecheeiem of thereactieve..

l. Water is evolved in the, reaction and the amount of the waterliberated is exactly chemically equivalent to the amount ofalkalireacting with the starch to produce the 2-monoalkali starchate. Theprovenover-all reaction is @Games meer@ @enorm-rezo 2. Starch readilyadsorbs alkalies and such adsor-ption complexes were isolated andcharacter@ ized by Karren, Pringsheim and others. This was veried inourlaboratory. At room temperature or even nearly up to 79 C., either inWater, in alcohols or in other solvents exerting some solvent actiontowards allralies the following reaction usually occurs:

Such adsorbed alkalies are readily lost to give the adsorption compoundsanalyzing to. be dif amylates, triamylates etc.

Portions of our inventions are based on the fact discovered by us thaton heating, in a system which aids the removal of water either bydilution, by evaporation, orby reaction, this complex can be decomposedinto the compound claimed and water as:

(cHwoyNaoH) (Genoma) -i-Hzo As stated above prior hereto this complexhad been formed. However, no one had heretofore converted the complex toa. starchate. n order tc de sc, it iS necessary 'c c separate theecmplex out of the solution (jat least'remove the Water from thecomplex) and then in heating to 8i" C., make provision for removal ciWater as stated above either by dilution, evaporation or reaction.

Dilution is obtained4 by using solvents; distillation or evaporationremoves water from the reaction mixture; and reaction removes water byabsorption. For example, by the use of sodium alccholate the water isromoved to produce more alcchcl and alkali asl v3. The position ofreaction is on C`2. 2-monosodium starchate reacts easily with methyliodide at temperatures of 8 0 C. or higher to yield 2- znonomethylstarchate. Y

This 2-mcacmethrl. eierchate may then be live .c lrclyzeel i9 yieldgeecncmethvl glucose i Such sugar was characterized as follows:

l. No osazone reaction under usual conditions.

2` Phenyl hydrazone crystallized in needles, M. P. 176 C. and (a)D=-12.4in pyridine which are the constants given in the literaturerfor 2-monomethyl glucose phenyl hydrazone.

3. Crystalline monomethyl glucose melted at 157 C. and (a)D=66 .0 inWater which are the constants given in literature for 2-monomethylglucose.

No other sugar, methylated sugar or sugar derivative could be isolatedfrom the hydrolysate.

8 Crystalline.prceucieieeleiee eccciicied. fer Sci-9% oi* the calculatedquantity obtainable freinv the monomethyl starch. The obvious fact' thatthe mother liquors. still contained appreciable amounts of our productleads us to conclude that the reaction occurs on C -2 only.

4. Surprisingly enough the water formed in the reaction comes about asfollows: The starch contributed the and the NaOH contributed the H.

substance analyzing to b e monosodium stercheiemer be preparedciieliquid emmenie and' metallic Sodium. but this. cempcurid is dif*ferent and distinct fromthel one heretofore. de-

'Scribeeesieehewri by. thefellewee (fr-eccessi??? siecle@ starchate) 4.ceereseie cee; cececieec Nel @,ffeieeilivl. staccate) Reaction l abovegoes only as. indicated. In contrast to cellulose and othercarbohydrates, starch yields only a monosodium starchate when treatedwith metallicb sodium in liquid ammonia` The position occupied by thesodium was blocked in Reaction 2 so that it would not be available forreaction with the process previously described herein. However, when theproduct of Reaction 2 above was subjected to the reaction previouslydescribed herein, the same reaction proceeded smoothly and completely toits limit as indicated in Reaction 3 above. The position occupied by thesodium of Reaction 3 was blocked by methylation in Reaction 4. When theproduct was again subjected to metallic sodium in liquid ammonia(Reaction 5 above) a second hydroxyl group is reacted which whenmethylated yields a trimethyl starch in Reaction 6 above.

If, however, we reverse the order of above reactions we have:

It ls obvious that the nonfaqueous sodium hydroxide reaction isconcerned with a position which is not involved in the' reaction withmeielliecedilim ansi, liquid emmeriiaf The Z-elkeli metal Stechctes medewith alkali metal hydrciees es describedU above, undergo. ibs Williamson.ether reaction to. ferm derivative products. The-following typicalprody ucts have been produced by us and are illustra# tive.

In each case'the 2monosodium starchate used was made in accordance withthe method described in said co-pending Gaver applications Serial No.357,995 and Serial N o. 707,318.

Z-alkali metal starchate or an vequivalent starchate compound andconverting it by appropriate treatments: For example, by reacting a2-monosodium starchate with a salt of the metal of which a starchderivative'is desired various 2metallic starchates are synthesized. When2- I monosodium starchate is chemically reacted with certain compoundsthere may be formed by double decomposition many other sta-rchderivative products.

Thus as pointed out in the co-pending applil' cations, an alkali metalatom can be substituted on the No. 2 carbon oi the basic starch unit byreacting or treating, in approximately stoichiometric quantities, starch(or similar natural or synthetic carbohydrates) with an alkali or alka-2.1

line reacting materialnthaving an ionization constant of. 2 105 oi-,.greateri in a solvent (containing enough of the alkali solution toproduce 0.04 N or higherlQat atemperature of 8G31G. or

higher (Withor Without agitation) fora' period l of two hours or longer.In such cases, a reaction will occur on the second carbon atom whichwill go practically to completion, provided alkali is present insufficient quantity to permit one mole of alkali to react with onemole'(l62 grams) of starch. Under certain described exceptions, thetemperature may be under 80 C. and under other describedAconditions thetime may be under two hours.4 A.

HYDROLYZED ORGANIC STARCHATES Referring now to the diagrams of thedrawings and especially'to Fig. l for a detailed description of some ofthe processes of our inventions, it may be seen that in the illustratedprocess, we react starch with an alkali hydroxide in a non-aqueoussolvent asis fully described above. Thealkali hydroxide may be sodiumhydroxide, potassium hydroxide, rubidium hydroxide, caesium hydroxide orlithium hydroxide. Ammonia hydroxide is unsuitable. solvent other thanwater which Will dissolve sodium hydroxide to the extent of 0.04 N orhigher. We have tested and found that the following solvents are allsatisfactory and we have found no nonaqueous solventwhich isunsatisfactory. n

Solvents used It hasv been found that any of the following alcohols maybe used 'to prepare monosodium starchate provided that certain othervariables are suiiiciently controlled as will be discussed later. Itmust be understood that not all these mentioned have the same utilityinthe process. However, any solvent which will dissolve NaOH, eveninvsrnall amounts, is a suitable vehicle in which to carry out thereaction provided that certain other variables'are suiiicientlycontrolled.

The non-aqueous solvent may be any BEST AVAILABLE COPYeiceholewhchwyewed Allyl Iso -amyl n-Amyl Sea-amyl l Telt-amyl' Anisyl Benzhydrol Benzoylcarblnol Benzyl K 2,3-butanedio'1 er:

Iso-butyl Sea-butyl Sec. butyl carbinol (p-tert. butyl phenoxy)` ethylCapryl Ceryl Cetyl 3-chlo1'o-2-propenol-l Cinnamic Crotyl CyclohexanolDecyl Diacetone Diethyl carbinol' Dimethyl benzyl car' binol Dimethylethynyl car-'- binol Dimethyl -n -propyl carbinol 'T12-ethyl hexanol'Furfuryl Di'nethyl 'isopropylcar- V'Dim'il I Di-n-propyl carbinolDi-isO-propyl carbinol Ethyl.-

Z--ethylbutylk l' Methyl Various polg/hydric alcohols also be usedEthylene glycolv Ethylene gylcol monomethyl ether Ethylene glycolmonoethyl ether Ethylene glycol Vmonobenzyl ether Ethylene glycol mono/`butyl ether' Diethylene glycol Diethylene glycol monomethyl ether.` l

It is clear therefore Di-propylene glycol Glycerol' l Glycerol d-n-butylether Glycerol a,a dimethyl ether Q Glycerol .afy diphenyl etherGlycerol a-.monomethyl ether Hexamethylen'e glycol Propylene glycolTriethylene glycol Trimethylene glycol that all non-aqueous solventscapable of dissolving the alkali to an extent comparable with thedissolving of sodium hydroxide to the extent of 0.04 N or higher-aresatisfactory. Step one of the process illustrated in Fig. l thusproduces a 2-monoalka'listarchate having a formula:

Ho cHlcHtoH-x As a second step. o

f the process disclosed in Fig. 1, we treat. the 2-1nonoalkali starchateA dlspersing solvent may be used if desiredbut is unnecessaryad Thereactants may be agita-teder not. as desired.; Pressure may beappliedLorpot, as desired. Thevzrrnonoalkali starchatejmaylL-be treatedin othermanners with the organiwcorrrpounds if desired- ;Inthedrawingaasegamples We have designated tthese reactants as 'orgtanichalides, but any organic compound containing@ replaceable halogen orsimilarly reacting rgroup is satisfactory. For instance,dimethylsulfate,

m 4palrjaffins, organic. phosphates, acetates, befnzoatsetc. aresatisfactory. As further ezarfiles-of the reactants Whichuf'ill re u L'nalkali metal or metallic starhatv'tdfprodgce the correspondingZ-'rrioiioe'thersA oij` such"oarbohydrates, the following may amylnitrite, ni

be mentioned; Acetodichlorohydrin Allyl bromide Allyl chloride Allyliodide n-Amyl bromide Iso-amyl bromide Iso-amyl chloride Tert.'-amy1chloride Amylen'e 'dichlor''de Iso -ainyl -"iodide Benzalacetophenonedibromide Benzal chloride Benzotrichloride Benzyl bromide Benzylchloride. Bromo'acetic"acidA w- Bromoaceto--'aph- .thoe v l"-Bromo-n-'butyric alcid Z-brorno-'I-chloroirv1...1921112.-.,Bromec'yclohexenje -Bromoeihy1-ethr -Bromoethylplienyl 'ether Bromoformm2-broxr1o octane i n p-Bromobhenaoyl bro mide Bromopicrina-Bromopropionic acid -Bromopropionic acid 'y-Bromopropyl phenyl...ether a-.n-Valerlcfacid -Bromo-isovaleric `acid. i .nButyl bromideIso-butyl bromide Sec-butyl bromide ,-Dibrom'obutyric acidv2,3-dibrornopropene ,-Dibromopropionic acid ',-y-Dibromopropyl a1-cohol 3,5-dibromopyridine ,-Dibromosuccinic f acid Diohloroacetic acidTert.butyl bromide n-Butyl chloride Iso-butyl chloride Seo-butylchloride Tert.butyl chloride n-Butyljchloroacetatc Iso-butylchlorocarbonate a-But-ylene bromide -Butylene bromide Iso-butylenebromide n-Butylidene -chloride n-Butyl iodide 'lso-butyl iodide Sec.butyl iodide Tern-butyl iodide Cetyl .bromide Cetyl iodide ChloralChloroace'tarnde Chloroacetdietlylamide'm l Chloroaceti Chloroac'etho/eChloroacretojfn rile Chlorobutane -ChlQrQ'biityri. acid^f-Chlfrbuyromirie Chlorqyldhexane. -Chlofroethyl acetate--Chlomniethyl'- chloirocarbonate @morada Chloropicrinxc-Chloropropionic acid Decamethyiene "liremide .Y

ether ,'Di chloroisopropyl ether Epibromohydrin Epichlorohydr'n Ethylbromide Ethyl bromacetate tyrate tarchate' having a BEST AVAILABLE COPYpecially the westers:`

dispersing solvents may also be used: se-'anim 'beijgefe iidiyiey'ciohexe n- Butyl 'benzene lHexa'df'ec'a'ne Seo-butyl benze 'Lig'roinTera-'butyl 'benzene Methylcycloh'exane 'Cumene Nonane .Cyclohexanel1-Octane 2,7-dimethy1 octane Iso-octane BEST AVAILABLE Colei 13n-Pentane Trimethy'lethylene Petroleum ether 2,2,4-trimethyl pen- Propylbenzene tane Tetraisobutylene Triphenyl methane Tetradecane o-XyleneToluene m-Xylene Trifisobutylene p-Xylene Trimethyl butane and variousothers. A The following ketones may also be used:

Acetone Methyl butyl Acetophenone o-Methyl cyclohex- Anisolacetone anoneBenzalacetone m-Methyl cyclohex- Benzophenone anone Benzoylacetonep-Methyl cyclohex- Diethyl anone Diisopropyl Methyl ethyl Ethyl phenylMethyl hexyl Ethyl undecyl Methyl n-propyl Methyl amyl and variousothers.

The following ethers may also be used:

Methyl iso -propyl and various others.

By these various lists we do not mean to exclude any other dispersingsolvents.

As step three of the process shown in Fig. 1, we react 2monoorganicstarchate resulting from step two with an alkali hydroxide in anonaqueous solvent in the same manner as in step one with the diierencethat the temperature is raised to 115 C. or higher and provision is madefor the removal of water. The same solvents as are used in step one aresuitable; the same alkali hydroxides are suitable. The alkaline reactingmaterial should have an ionization constant of 2 105 or greater in asolvent containing enough of the alkali in solution to produce 0.04 N orhigher at a temperature of 115 C. There may be agitation or not asdesired. The reaction should continue for a period of one hour orlonger. There must however be a provision for removal of water formed inthe reaction. This is most important and the provision for the removalof water together with the higher temperature distinguish this step fromthe requirements of step one. It is essential as stated that the waterevolved in the reaction be removed as rapidly as formed and thereforeonly those alcohols boiling at 115 C. or more have any utility assolvents in the reaction except in special cases Where vSome other meanshave been devised to remove the water. At 115 C. the water is removed byboiling or distillation. At temperatures below 115 C. special means mustbe provided for removing the water. This step of the process produces a2-monoorganic, 3-monoalkali starchate, having a formula of H OCHgICH(CH-)(CHOM^)(CHOR1) C-Y-O- The fourth step civ the illustrativeprocess is similar tothe secondstep. It comprises the reaction oftheproductief the third step with an organic reaction. This may be the sameorganic reactant as used in connectionwith the second step; prit maybe-a different organic reactant. It may'be any one of the organichalides or similar reactants-mentioned above in connection withstep'two. :'On treatment of the product, there is a reaction to producea 2,3-diorganic starchate having a formula of y 0 HHcmimcm-xononuxonoR1)cc- In step,l as inl thepreceding step, thetemperature should be'kept at 115 C. or higher and precautionsjshould betaken to prevent water contamination.'

The fifth step of the illustrative process comprises .the reaction ofthe product of the fourth step with anlalkali metal dissolved inammonia. As pointed out above, this process which comprises-.thefth stepis a step known inthe prior art. 'TI-IoweverI we combine it with theprevious steps of. this .process and the combination becomes .a newprocess because it involves a new combination of steps,jsome of whichare old and some f which are new. Moreover, an entirely new product isobtained by this reaction. By it, we produce a 2,3-diorganic,6-monoalkali starchate having a formula of The sixth step of theillustrative process is similar to thesecondiand fourth steps. In it wereact the product .of the iifth step with an organic reactant.: .Thisreactant may be the same as used in step two vor the same as used instep four, or may be entirely different from the reactant used in thosesteps. By this sixth step reaction, We produce a 2,3,6-triorganicstarchate having a formula of o. H RIHOomomcH-XCHORUXCHORI)cc- Theseventh V step of the illustrative process comprises the treatment ofthe 2,3,6-triorganic starchate produced in the sixth step with analcoholic acid solution to obtain a 2,3,6-triorganic, a-alkyl glucosidehaving a formula of Rmo oHzcHHoHxcHoRHi(cHoRooHoRlv This glucosidehydrolysis of the starchate is somewhat similar to the glucosidichydrolysis of starch according to the prior art. However, we combinethis step with the preceding new and old steps of our process into a newcombination of steps. By this entirely new combination process weproduce entirely new products.

The eighth step illustrated comprises an etherication of the product ofthe seventh step to produce a 2,3,4,6tetraorganic, a-alkyl glucosidehaving a formula of Y RufooHzJJmCHoRvxoHoRHMCHORIXCHORW) Aprocessanalogous to any one of several of the priorart processes may be used inthis step in combination with our other new and old steps. For instance,prior to our invention starch has been methylated (1A)` by the use ofmethyl iodide products einen riiayjbelsyntnesizedfwour new rdcs'ss.following ."discus'sion this 'paragraph refers' oiil'yfto thenumberfproducte which may be synthesized byl processes follow- "the 'o''the "process :de scribved Labove as 'constituting Asteps one tt reisst,of j tue 'process disclosed in l-ig"."ffl llhe jnurnbe'r 'o'f reactants'liasses-ove sssui'tabiieforrescucnfm stepsftwo. 'four aansu:-inciueespprqsimeteiyeieiitfdenva- BEST AVAILABLE COPY 'aecomooiganic'radicals (actually there-'areaigreat rnany indre) whichniaybesubs'titutedeitirer as RIIRH or RHR iline;slnu'cl'i"asia'r'iy*oneof,ti'xera" di^cal s r'ri'ayibe substituted for R,I,`the`re"are"eghtydifferentornpoun'ds which maybe synthesizedbythe "iirst' two steps."Inasmuchas' anyof .the-radicals may in each case be substitutedas*RU7there are (80)2 or 6400-compoundswhichmay be synthesizedbytlie--firstfoursteps. .Inasrnuchas any of these radicals `may besubstituted as R111.

be synthesizedhy"V therstvsixfsteps; iflllriscarrying =tne.!prooessfnnly-'through Athe1sixtlfr :stoptenf'ables f us to produceapproximately @500,000 new `sts'ircliates. Bysmeansioffthc:seventh Stepwe -are r'able "to "ad'dfonto the TNO.; l '.'carbon aanotheriorganic'r-adc'al, '.llnasmucheas'ithi's may -becany "organicradical-which? formssanf.organiccalcohol, the number of newcompourrdspossible'byvthe utilization of the seven steps rises to anumber of many million new compounds. inally, by the'l O l A RUIOCH2C`H(CHOH)(CHORU)( CH OR) CH OH We 'may' th'en treat 'lthis 2,3,6Ltriorganic glucose to etherify it by the use of a process anal--agous to .the above' nientionediprocesses'involvingr the`use f(1)"methy1'dde and silver-oxide; (2)'f'dimethyl' sulfateand sodiuiri`hydXlde;"(3) 'dimethyl sulfate 'and barium hydroxide and can producefaf2l34li6 ing a formula ofI RInOCHzCI-IORMXCCHORIV) I i. (CHORH)(CHORXCED We may then condensethis 2,3,4,5,6pentaDllgaIlic glucose bythe use' 'of condensingjagerrtstoproduce a large number ofdifferentg'jfi-pentaorganic glucose derivatives having iaformula'ofRmoceztcnoawi conoav) "i jtCHoRH) (QHQEIICHZ Instead of condensing the2,3;*l'5-.pentaorganicIglucoserwenraysubject it to Wohlssdegradationprocess to'lproduce a LSA-pentaorganic riboside havingaalfermula ofRmocrrstcnplvilcuoaw) (surnam-rondas We inayfalsosubjectthe glucosesand-the various organic starchates of the processcsrillustratedjn Fig. ltosreactions such `as esterication, oxidation, and"redutionftdproducestill other cornpcunds.

The .processes .-iniicated in Fig. 2 parallel -to some extentthose'iescribed in connectionwith Fig. l. Howverfjsheorder of the steps'ofthe processes disclosed 'fin Iig. 2 are differentlfrorn the orderof'thesteps disclosed in Fig. l, so that some new and diierent productsare obtained. Also, several vothergbranch processes-are :disclosed Thus,while some ofthe. products obtainedtbyihe processes disclosed glgig. 2are the same -a:s`;the products obtainedjlbythe processes 'ofFiggkLstill there are disclosed new processes for jproducing the samenewcornpounds as well asnewprocesses for producing many other compounds',not produced by the processes describedinconnection .vith-FigrLvthe-process described: in connection Withiig.l 1,.` their'st'step of'the Kprocfesses-illustrated in-Fig.' '-2 is the'rea'ction oflstarchlwith an Aalkali hydroxidejiiissolved'in an -non- 'aqueousrsolvent Evtoproduce a 2,-monoal1rali pentaorganicslucosejhavl j n so orrronmr-e)(on-OMA) (cnoau lo 'It-will'f-benotice'd that lstep'fthree is-` 'similar`to-step"'ve disclosed Fig. 1. "Theresult.' how- Aever,'islthatAtheelkali metal isf attached -toboth the-'N023 carbon atomiarid'tlie'Nofcarbon -with 'theJ result thatl the-'product ofeitherA stepf` three'is#entirelyliiiferentffrom':fthe product -of veither `stepfthreeoi""step" 1ive 'of'the previously described process. FStep four is'thefreaction'of this' produ'ctlwith an organicfreactant toj producea"2',3;6 triorganicl 'starchat havinga formula' of R110onzen(CH-XCHORIWCORcio nlthouglrthe designationof the` organic radicalsin the formula' for this' 2,3;6-t'riorganc starchate BEST AVAILABLE COPYs 'shown in'Fi'g. 2 differs from that ofthe 2,3,6- triorganic starchateproduced by the rst six steps of the process shown in Fig. l asisdisclosed by a comparison of the formula, yet the product may be exactlythe same, depending upon the choice of the organic reactant for reactionin steps two, four and six of the first process described, and forreaction in steps two and four of the processes described in connectionwith Fig. 2. Thus the products produced by this process may be producedby the'process disclosed in Fig. l, although the process diiers becauseof the diierent order of the steps. Moreover, because inthe processdescribed in connection with Fig. 1, diierent organic groups may beplaced on carbon 3 and carbon 6 a greater number of different organicstarchates may be synthesized therebyi'thanby -the process4V inconnection with Fig. 2.- As explained in connection with Fig. l, theZ-monoorganic starchates and the 2,3,6-triorganic starchates synthesizedby the last described process may be further similarly reacted toproduce other products by glucosidic hydrolysis, acid hydrolysis,esterification, etheriication, condensation, degradation, oxidation,reduction and so forth.

Certain other processes according to our inventions, are also disclosedin Fig. 2. For instance, the 2-monoorganic starchates may be subjectedto 'glucosidic hydrolysis, to produce 2-monoorganic, a-alkyl glucosides;2-monoorganic, a-aryl glucosides and; 2-monoorganic, a-aralkylglucosides (the aryl and aralkyl glucosides not being speciiicallydesignated in the figure) having formulas ofHocHicHwHoHxCHoH)(cHoRlioHoRu These products are different from anypreviously described. They may be further etheried to produce a2,3,4,6tetraorganic glucoside having a formula ofi Ruloeinen(CHORHIMCHORHIXCHoRbcHoRu While products of the same type as thelast named glucoside may also be produced by main processes shown' ineither Fig. l or Fig. 2, yet the process last described is a diierentmethod of producing such products.

Another process disclosed in Fig. 2 is' the acid hydrolysis of the2-monoorganic starchate by the use of Water and acid to produce a2-monoorganic glucose having a formula of 0 HOCHZCEHCHOHXCHOH)(GHORI)HOE products may "also'be'produced by the process shown'in Fig. 1 byetherification of the 2,3,6-triorganic glucose.` The'process disclosedin Fig. 2 may' in some instances, Where applicable, be a more economicalAprocess than that shown in Fig. I because of the elimination of some ofthe steps. This product may also befurther reacted-.by condensatonanddegradation processes and so forth.

Again the 2-monoorganic, 3,6-dialkali starchate produced by the thirdstep of the main process disclosed in Fig. 2 may be reacted with ametallic salt to produce a 2-monoorganic, 3,6-dimetallic starchatehaving a'io'rinula of MocmomcH-MoHoMxcHoRl)o o Many of these metallicstarchates may be further reacted to replace the anion groups ofmultiple valent derivatives. Fig. 2 also illustrates that any of theorganic starchates of Figs. 1-5 inclusive, may be subjected toglucosidic hydrolysis by aryl or aralkyl alcoholic solutions as Well asby alkyl alcoholic acid solutions. For instance the 2,3,6- triorganicstarchate may be subjected to glucosidic hydrolysis to produce either a2,3,4,6tetra organic a-aryl glucoside or a 2,3,4,6tetraorganic d-aralkylglucoside as shown in the figure.

In the processes disclosed in Fig. 3 the rst step diiers from the rststep of the processes disclosed in Figs. l and 2. Although certain ofthe same end products may be produced either by the main processdisclosed in Fig. 3 or by the main processes disclosed in Figs. 1 and 2,the processes themselves are different, some intermediate products aredifferent and some alternative processes produce some differentproducts. The processes of Figure 3 by reason of the change in theinitial step are obviously different from the processes described inconnection with Figs. l and 2. .In the main process disclosed in Fig. 3starch is reacted with an alkali metal dissolved in ammonia to produce a6-monoalkali starchate having a formula -of o H wocmcmcH-i(ononucnomloThis -monoalkali starchate is then reacted as previously described withan organic reactant to produce a -monoorganic starchate having a for-`mula of o A /H Rio(salomon-xenon)(cHoHjC-otease-4 ,use

BEST AVAILABLE COPY l Thisstarchate issimilarly reacted with an organic:reactant to produce a 2.6-drga10 starchate; havingr a formula of l O /Hl `RCH2U`I CH)(CHOHXCHORH)O-o..

This .2,6-diorganic starchate is then reacted Withan. alkali hydroxidein a non-aqueous solvent. In this step, as stated above in conneCtOnWith Fig. l and Fig. 2, it is necessary to take adequate precautions forthe removal of Water and against Water contamination. The temperaturemust `be raised to 115 C. or higher so that Water is driven off bydistillation or other provisions made for 4the removal of water. Theproduct is a 2,6-diorganic, 3-monoalkali starch- `ate'having a formulaof I O 7H' RiooH2oH(cH-)(CH0MA) CHORiou-O By reaction with an organicreactant as in the processes previously described a 2.3.6-tr0rgan10starchate may Le produced having a formula of -o /HR10oHioHroH-XCHORIH)(CH0RH)o-O Although this formula may appeardifferent from that of the products produced by the previously describedprocesses, yet it may deiine exactly the same products produced by suchdiierent processes. This 2,3,6-triorganic starchate may, ofcourse, bereacted by glucosidic hydrolysis, acid hYdI'Olyss, esterication,etherication, condellsation, degradation, oxidation, reductions andS05-forth.

vThe -monoorganic starchate and the 2,6- diorganic starchatemay also bereacted by glucosidicghydrolysis, acid hydrolysis, etherifcation.esterication, condensation, degradation, oxidation,. reduction and soforth to produce other COmDOunds not previously mentioned. The G-monoalkali; starchate; the S-rnonoorganic.. 2. monoalkalistarchate; andthe 2,6-diorganic, 3- monoalkalil starchates may be reacted with ametallic salt to produce corresponding monometallic starchates which maybe further reacted yby the replacement of. the anion groups of multiple.-valent derivatives.

The processes disclosed in Fig. 4 are similar ln many respects to thosedisclosed in the first portion of Fig. 1. That is to say, the first vesteps 0l' .the main process shown in Fig. 4 are exactly the same as theiirst five steps of the DIQCBSSidSClOSed inFg. l. Thus starchisreactedwith an alkali hydroxide in a non-aqueous solvent; to produce a2-monoa1kali starchate.' This 2-monoalkali starchate is convertedbyreaction With an organic compound to produce a 2-monoorganic -starchateThisis reacted again with alkali hydroxide in a non-aqueous solvent at ahigher temperature to produce a 2-mono- Organic, 3-monoa1kali starchate.This, is re. actedwth an organic compound to produce a 2.13,*-d01ganicstarchate. This is reacted with angallali metal dissolved 'ammonia toproduce ar-ZdiOrganc, -rnonoallraliV starchate having er formula of-However, alternativevprocesses Qdisclosed lin Fig. 4 are different fromany'of the processes previously disclosed in connectionwith Figs. l, 2and *Y Thus we show thatthe lZ-nnonoalltali starchate maybe reactedwithV a metal salt to 20' produce a' 2i-monometa11ic; i stammte-.a1haring .-:c formula of The 2-monoorganic. 3-monoalkali starchate. may bereacted with a metallic saltv to produce a 2-monoorganic,S-metalliestarchate .havingra formula of 0 no omilimol(CHoMuoHoRucor-The. 2,3-'diorganic :G-monoalkali star-chateumay be reacted with ametallic salt to produce a 2,37' diorganic 6-metallic starchate .havinga iormul'a Any oney of theabove described.monornetalllo starchatespmaythen be reacted toeiect replacenient of aniongroups: of multiple,valentgderivatives.

The 2-monoorganic starhate;` or the' 2, 3fdi,- organic starchate; may beethered, esteried. oxidized, reduced, and/ or subjected to. a Grignardreaction and so forth to produce products which are entirely differentfrom,anypossibleA under any prior artpprocesses and manyWhichareentirely diierent from anyprocess described incong nection withFigs. l to 3 inclusive.

The 2-n1 o: ioorganicA starohates .maypbe sub- `ected to glucosidichydrolysis by. alcoholic acid solutions to produce' z-monoorganic,a-alkyl glucosides, 2-monoorganic, a-aryl glucosides, or 2monoorganic-,'a-aralkyl glucosides '.With a formula of H0CHMWCHOHKCHOHXCHORUHOB" The2,3-diorganic starchates may bei subjected to gluoosidic hydrolysis byalcoholic acid solutions to produce 2,3-diorganic, a-alkyl glucosides,2,3-diorganic, a-aryl glucosides, or 2,3-diorganic. a-aralkylglucosideswith formulasof4 Ho oHuliHtoHoH)(QHoRlooHoRr) 01101211# Y.

The 2-moncorganic starchates maybesubjected to. acid hydrolysis ,by theuse vof water: andan acid to produce, Z-monoorga'ruc glucoseshavingformulas of j ,w 0. HocgicmcHomccsoHxcnom013011 The :2,3-diorganic;starchate -maycbe subjected to acid .hydrolysisby the-use. ofWater:-and.-an acidito. produce 2,3-diorganic glucoses, having.

formulas of-ll Hocmciirorioiironoan)(oHoRocHoH' BEST AVAILABLE COPY 21c-aryl glucosides, or G-monoorganiec-aralky glucosides) having formulasof These glucosides may be then further reacted by etherication and soforth. Or the 6-monoorganic starchates may be reacted With Water andacid to eiect acid hydrolysis of the starchates to produce 6-monoorganicglucoses having formulas of These glucoses may be further reacted byetherification, condensation, degradation and so forth. Moreover, the-monoalkali starchates maybe reacted with a metallic salt to produce6mono metallic starchates having formulas of H MooHigJmCH-MCHOHXCHOEDlo-These G-monometallic starchates may be further modied by the replacementof anion groups o` f multiple valent derivatives.

Above in connection with Figures 2, 3, 4 and 5 we have described thereplacement of alkali metals with non-alkali metals by reaction of thealkali starchates with metal salts. In each of the cases specified wecan, if we Wish, vuse a non-metal inorganic salt as the reactant insteadof a metal salt and obtain instead of the nonalkali metal starchatesdescribed in connection with said Figures 2, 3, 4 and 5 correspondingnonmetal inorganic starchates. 'I'hus in fact we can react the alkalimetal starchates with any salt. organic or inorganic, metal or non-metaland obtain corresponding organic or inorganic, metal or non-metalstarchates.

While the above are believed to cover the main processes involved in ourinvention disclosed herein, the following resume of the hydrolysisproducts of the starch ethers synthesized by our processes will behelpful.

We have described in this application methods of synthesizing thefollowing types of starchates and starchate derivatives in connectionwith the figures indicated:

Alkali starchates: Figures of drawings 2monoalkali 1, 2, 4 -monoalkali3,

Organic starchates:

2-monoorganic 1, 2, 4 -monoorganic V3, 5 2,3-diorganic 1, 42,6-diorganic 3 2,3,6-triorganlc 1,2, 3

Inorganic non-alkali metal and non-metal starchates:

2monornetallic 2, 4 -monometallic 3, 5 Inorganic 2-mononon-metallic 2, 4Inorganic 6-monononmeta1lic 3, 5

Mixed organic alkali starchates:

2rnonoorganic, 3-monoalkali 1, 4 2-monoorganic, 3,6-dialkali 22-monoalkali, 6-monoorganic 3 2,3-diorga-nic, G-monoalkali 1, 4

` 2,6-diorganic, 3-monoalkali j 3 22 Mixed lorganic-non--alkali metalstarchates: v21nonoorgani'c, 3-monometallic 2rnonoorganic,3,6-dimetallic 2-monometallic, 6monoorganic 2,3-diorganic, -monometallic2,6-diorganic, 3monometallic muscolo-nh' Glucosides:

2-monoorganic, alkyl- 2-monoorganic, aryl- 2monoorganic, aralkyl--monoorganic, alkyl- 3 -monoorganic, aryl- (i-rnonoorganic, aralkyl-2,3-diorganic, alkyl- 2,3-diorganlc, aryl- A 2,3-diorganic, aralkylj`2,6-dlorganc, alkyl,

v' 2,6-diorganic, aryl- 2,6-diorganic, aralkyl- 2,3,6-triorganic, alkyl-2,3,6-triorganic, aryl- 2,3,6-inorganic aralkyl 2,3,4,6tetraorganic,alkyl l, 2,3,4,6tetraorganic, aryl- 2,3,4,6tetraorganic,aralkylcru-concu Glucose derivatives:

Products of-Esterication. condensation, oxidation, reduction, and Wohlsdegradation-of glucoses shown above 1, 2, 3, 4,5

As was demonstrated previously herein (assuming a list of only eightyorganic radicals available for reaction (i. e. substitution as RI R1IRIII RIV and R") it is clear that we have taught the synthesis of eighty2-monoorganic stai-chates; eighty 6m0noorganic starchates; sixty-fourhundred 2,3-diorganic starchates; sixty-four hundred 2,6-diorganicstarchates; and ve hundred twelve thousand 2,3,6-triorganic starchates.Each of these starchates may be hydrolyzed to glucosides which anyalkyl, aryl or aralkyl alcohol acid solutions so that many million suchglucosides may be synthesized. Each of the starchates may be hydrolyzedby an acid water solution to form an equal number of newV glucoses. Eachof these new glucoses may be etheried with any appropriate etherifyingagent to synthesize many million new glucoses. Each of the monoorganic,diorganic and triorganic strachates listed above may be esteried,dehydrated, condensed, oxi-. dized, reduced, subjected to Grignardreaction, and exhaustively etherifled. The open hydroxyl groups of suchstarchates may also be reacted by the replacement of the hydrogen of thehydroxyl group by active metals, acid halides, organic acids, organicacid anhydrides, alkyl hydrogen sulfates, Grignard reagents or by thereplacement of the hydroxyl group by hydiodlc BEST AVAILABLE CQpy acid;hydrobromiofacid, 'hydrochloric cid", sul"- =furic acid,niti'ic acid.'Frexample; th'e'hydroxyl 'groups ofsuch organic starch-atesemaybe re--acted -bydehydration to produce unsaturated .'derivatives;by'oxidation' to giveketones';"by condensation with aldehydesv to givealdol-type products; by condensation with reagents reacting withaldehydes' t'o 'produce another' series of "glucose derivatives.` Theal'dehydegr'oups ormedmay be (1) oxidizedto 'the carboxyl'tc formaseries of substituted gluconic acids With their correspondingderivativesof salts, esters, -timides', acid chlorides, anhydrides,lactones,'and la'c'tides', etc.; (2) reduced to a primary alcohol groupgiving another position (six in all) over which We have control; (3)reacted with Grignardreagents, hy- 'fdrocyanic acid, sultes,. ammonia,etc.-to `produce another series of compounds; and (4) replaced .b'y' thesb'stitu'tionby halogens, .hydroxylamine, hydrazine', phenyllhydrazine,and various .substituted h'ydra'zmesy etc. Y

' From' the above it willfbe clear Vthat-.it is impossible togive'examples oflthe synthesizing of all of the products possible by ourimproved process or even to give examples of all of the hundreds cfproducts which Wehave actually synthesized.

Following are examples of the synthesis of various'prodcts by the use ofprocesses of our invention.

Inasniuch as certain steps of the procedures involved'in' rr'iany'of theexamples were identical or'substantally identical, we set out now aseries of directions or procedures which are- .followed in performingsuch steps. These directions or procedures are designated asProceduresleli, inclusive andin each of the examples; we 'have merelystated that certain of thesenprocedures were employed. Thereby Wehavenotonly reduced the work of Writing out the examples but have also,we believe, presented the examples in a manner by which they maybe'more-readily understood; Followingare the 'tlfirten proceduresrefenedato.

PROCEU'RE. I Preparation of 2-sodium starchate a 1:0001 r'lf.threeenecked .flask fittedwith aneiiicientagitator, al* thermometer andarefiix condenser, place .the following :v

l''g'ramsof starch Y 22- grams offsodium hydroxide 500 mi; butanol Heat'thisimixture to- 85* C. fo'rZ'hoiIrsfwitlfi vigorous". agitation: Filteron suction, wash' with butanol'andthen with toluene; The' product', 'atthis-stage Gambeused .directly Procedure' '4. Theproduct'm'ay;khoweverg'be dried toiproduce' 2- sb'di'unrstarchate. The 2-sodiumstarchate'm'ust be' protectedY from moisture and carbon" dioxide duringfiltration, 'processing and drying; Drying' dan be best' 'effect-.edm avacuum -at temperatures below 1'0012.

- l yPROCEDURE -2- i ni'ailcoo mi. Gleisen flask-fitted with an efflowing:

10o grams of staren A gqgvramsofsodiumhydroxide 750 mlfbutanolfsivviydistifwitif vigorous agitation-until menig- -irl"Procedure 4.'Ih'ejdryproductisnnstable.`A

I f 'CL2 is .occupiedby Rstlien the' amount of Y'sodium hydroxide shouldbecut'to. 20 grams:

PROCEDURE 3 Preparationof 6scdiumstarckcta o on any free hydroylfgroupwith, theerception of native starch in which' case itis only on C-6)1000ml'. three-necked fiask' cited with' 'an e'cient agitator,ari-ammonia inietanda-stoppcr,

and immersed QlinchesjinaDr'y Ice'aceiion'ebznhl placethefo'll'ovving':- j'V Pass dry ammonia gas 'intothe la'sknntil 500 ml.of liquid ammonia havejbeen condensed.

Introduce 25 grams of dry starch which soon disperses in theliquid'ammonia under 'the' influence of agitation. Add sodium wirepiece-'wise until the' mixture turns blue (3.5 'to'3'.'7 grams). Theexcess sodium, indicated by the iblnecolorfmay be destroyed by small.amounts of carbo'n'dio'xide.

TheV ammonia isremoved by evaporation and theiproductmay be useddirectly in'Procedure 4.

100 grams of starch (converted into gthesodium s tarchate) 200 ml.toluene 100 m1. of .the organic halide Thismixtfure is placed in a 1000mi'. bomb (preferably glass' lined) sealed tight and autoclaved at 100C. forabout four hours. l

The supernatant liquid is decan'ted (or'ltered) off` and the productrepeatedly extracted hot with anhydrous. butanol to remove the NaXformed.

l This purified product is then washed with an# and then dried.

PROCEDURE 5' Glucosidic.lig/tirolys'isfA In a 2000 ml. three-necked.flask -iitted ,withan efficient agitator, a thermometer .andal'refl'u'x condenser, place the following-'i 1500anhydous alcohol(ac'cordingto the glucoside desired) hydrous toluene Pass in dry'HCl gasuntil the solution-becomes i. e., extraction, crystallizationoriractionalgpre- BEST AVAlLABLE COPY PROCEDURE 6 Acid hydrolysis In a2000 ml. three-necked flask fitted with an eiliclent agitator, athermometer and a reflux condenser place the following:

100 grams of starch (converted. into the starch ether) 1500 mi. 0.5% HC1solution Reflux with agitation until the optical rotation becomesconstant (48 to 72-hours At the completionof the hydrolysis, add 50grams of silver oxides and the solution is concentrated under vacuum toa volume of 500 ml. and then filtered hot through a lter aid anddecolorizing carbon.

The solution is then evaporated to a sirup and taken up in alcoholWhereon the polyamyloses are precipitated. The alcohol solution is thenevaporated and the substituted glucoses are crystallized or separated inthe usual manner.

PROCEDURE 7 Etherifcaton according to the reaction ROH+R1X+NaOHRORI+NaX+HzO In a 1000 ml. three-necked flask fitted with an eflicientagitator, a thermometer and a reflux condenser, place the following:

100 grams of starch (converted into the derivative) '750 ml. 20% sodiumhydroxide 100 ml. organic halide Heat this mixture at 95 to 105? C. forfour hours with vigorous agitation. Neutralize the reaction mixture withHCl (1:1) and concentrate to a sirup under a vacuum. Take up the etherin alcohol and purify in the usual manner.

PROCEDURE 8 Wohls degradation [Cohen Part III, 4th ed., page 8, 1924.]

This method is standard and consists of the following steps:

1. The aldose is treated with hydroxylamine to give the oxime;

2. It is then acetylated (Procedure 9) to remove the water and to blockany unreacted hydroxyls;

3. Treatment with amoniacal silver nitrate removes HCN to form thealdose with one less carbon.

Since the saccharides described are generally 2-substituted the pentoseis found present as the glucoside at this point and may be isolated assuch in the usual manner.

PROCEDURE 9 Acetylation In a 750 ml. Erlenmeyer ntted with a lingercondenser place the following:

10 grams of starch (converted into the derivative) 300 ml. aceticanhydride 30 grams fused sodium acetate Heat this mixture just below theboiling point for about 4 hours. The unreacted acetic anhydride andacetic acid formed is removed by 261 vacuum distillation, care beingtaken as the mixture approaches dryness.

'I'he reaction product is removed by extraction with appropriatesolvent, recovered and purified in the usual manner.

PROCEDURE 10 Deglucoszdatz'on The glucoside radical may be easilyremoved by the standard procedure consisting essentially of allowing theglucoside to standat room tem-- perature with l N aqueous hydrochloricacid and the free aldose may be separated inthe usual manner.

PROCEDURE 11 Oxidation The glucose derivative corresponding to grams ofstarch is dissolved in 1000ml. 10% sulfurie acid. This mixture is placedin a 2000 1.1.11.: three-necked flask immersed in ice water.' With'eicient agitation 100 grams potassium permanganate is added in 5 gramportions. At no -time is the temperature allowed to rise over 20 C. Atthe end of the reaction period (about 2 hours) the excess KMnO4 isdestroyed by a stream of sulfur dioxide. The acid solution isneutralized with barium carbonate and the solution evaporated todryness. The barium salt of the gluconic acid is extracted with alcoholand the product finished in the usual manner.

PROCEDURE 12 Reduction The glucose derivative obtainedfrom `100 grams ofstarch is dissolved in 1000 ml. of A10 N methanolic KOH at 60 C. 400 ml.Formalin is then added and methanol added at such a rate that thetemperature remains between 60 and '70 C. When the temperature dropsthe'mixture is heated, withagitation, and the tempera'-f ture maintainedat this point for 3 hours and then cooled.

The alkali is neutralized with sulfuric acld (1 5) and the mixtureevaporated under vacuuml to a sirup. The product is extracted withalcoho and purified in the usual manner.

PROCEDURE 13 Preparation of phenylhydrazones The glucose derivative isconverted into the phenylhydrazone by dissolving in acetic acid and thentreating wtih phenylhydrazine base in 'the usual manner.Prolongedheating is vto f be avoided. Y

The crystalline hydrazone is purified lby Arecrystallization from dilutealcohol in the usual manner.

The procedures set out in detail above (with exception of those listedas Procedures l, 2 and 3) may be modified within wide limits withoutendangering the expected result.

Procedure 1 may be modified as described in copending applications butthe procedure given is the one we recommend for use in conjunction withthe other procedures referred to. ff

Procedure 2 may not be modified in any way other than relative to thealcohol used. The mixture must boil at temperatures of 118. to C. Otherdefined conditions are required.

|Procedure 3 may be modied somewhat as the requirements dictate4 but theproceduredescribed has been found to be generally most satisfactory:

The 'following enumeratedsteps are used to. prepare this glucoside.

1. Procedure-'l applied-*to -produce 2-sodium starchate.

2. Procedure 4-applied-withethyl bromide to produce; 2.-,ethyl.-.starchate f3.. Procedure .2 4applied :to produce 2.1ethyl, 3- sodiumlstarchate.

f4.- Procedure=4. appliedwith n-prop'yl bromide to produce .2-ethyl, 3.npropyl starchate 5. Procedure 3 applied to produce Z-ethyl, ,3-n propyl,-sodiumstarchate.

6. Procedure 4'applied with n-butyl bromide to produce 2-ethyl, 3-31-propyl, 6-n butyl starchate.

Alroce'clure.55 appliedwith methanol to ,producez -ethyL .3:11. propyl,6 -.n'.hutyl, -a-methyl-.D- glucoside.

-pmarennin Synthesis of vIZ--n butyl; 3n propyl, G-ethyl,a-methyli-D-glucosdc of lz-ethyz, .'s-benzyz,I a-methylrDfgl-ucosde Thefollowing Aenumerated steps Aare 4used to prepare this vglucoside by amethod consisting of a combination of -steps ditering `Afrom -ordiiering in orderfrom the steps ofthe method described inExamples 1 and2.

`1.'Procedure "3 applied Ato produce 6-sodium starchate.

*2. Procedure 4 applied with isopropylbromide to -produce -isopropylstarchate.

3. Procedure l applied to produce 2-sodi um, 6-isopropyl starchate.

`4.1P1ocedure 4 applied with ethyl bromide v'to produce2ethyl,6'isopropyl starchate.

5. Procedure 'Z applied with benzyl chloride to produce 2-ethyl,3benzyl, G-isopropyl starchate.

i6. 'Procedure 5 applied with methanol to produce Z-ethyl, Sebenzyl,6-isopr0pyl, ar-methyl- D-glucoside- Synthesis `li-isofpropyl `TheAfollowing enumerated steps are used .to nrellareiths glucosederiwative.

BEST AVAILABLE copy L Procedure.11s-applied v.to produce Zfsodumstarchate.

2. Procedure 4 applied with n-propyl bromide to produce 2-n propylstarchate.

3. Procedure 2 .appliedto produce 2-n propyl, 3-sodium starchate. n

4. Procedure-4 applied with isopropyl-bromide to produce 2-n propyl,3-isopropyl starchate'.

5. Procedure 7 applied with benzyl chloride-to produce-.Z-n-propyLs-isopropyl, ,fi-benzylgstarcm ate.

6. Procedure 6 appliedto. produce 21p propyl; 3-isopropyl, -benzyl,d-glucose.

rIhe Vfollowing enumerated; steps are V.used to. prepare this glucosederivative lby -a ,methodcopfsistirlgof a combination oisteps dieringAfrom or .differing in order from ,the steps .0f the method described inExamplei.

`1. Procedure 3 applied to produce 6-sodium starchate.

2. Procedure 4 applied with n-propyl bromide to produce 6-n propylstarchate.

3. Procedure 1 yapplied to produceA Z-sodium, 6n propyl starchate.

4. Procedure 4 applied with methyl iodide to produce 2methy1, 6n propylstarchate.

5. Procedure 2 applied to produce 2-methyL j3- sodium, 6-n propylstarchate.

6. Produce 4 applied withisopropyl bromide to produce `Z-methyl,'3-isopropyl, 6-n propyl starchate.

7. Procedure 6 applied toproduce 2 methy1i3` isopropyl, 6-npropyl-D-glucose.

.EXAMPLE YI SynthesszofzZ-.n propyl, .Ii-methyl, lifisobutyl-D- glucoseThe following enumerated steps are used to prepare thisglucosederivatiyeby a method consisting of a combination ofstepsdifiering from or differing in order from the steps of the methoddescribed in Examples 4 and 5.

1. Procedure 1 applied to produce 2,-sodium starchate.

2. Procedure 4 :applied -with v i1-propyl bromide to produce 2-n propylbromide.

Ali. .Procedure 2 .applied-.to -produce2-n propyl, 3- sodium starchate.

4. Procedure 4 applied with methyl iodide `to produce 12n propyl,Bemethyl rstarchate.

5. Procedure 3 vapplied #to produce 12-n propyl, B-methyl, 6sodiurnstarchate.

6. Procedurev4 .applied with isobutyl bromideto produce .2-n-propy1,3methy1, S- isobutyl starchate.

'7. Procedure 6 applied to produce `2n propy-i, 3-methyl,-isobutyl-D-glucose.

EXAMPLE'VH Synthesis of Z-monomethyZ-a-methyl-D- glucoside The followingenumerated steps are used to prepare this glucoside.

l. Procedure 1 applied t0 produce 2sodium starchate.

2. Procedure 4 Yapplied'with methyl iodide to duceZ-methyl-n-methyl-D-glucoside.

3. Procedure .5 applied with methanol toproduce-.Z-methylfa-methyl-D-glucoside,

BEST AVAILABLE COPY EXAMPLE VIII Synthesis of 6-monomethyZ-a-methyi-Dglucoside The following enumerated steps are used to prepare thisglucoside.

1. Procedure 3 applied to produce -sodium starchate. A

2. Procedure 4 applied with methyl iodide to produce 6-methyl starchate.

3. Procedure 5 applied with methanol to produce6-methyl-a-methyl-D-glucoside.

, EXAMPLE 1X Synthesis of 2-methyl, -ethyl-a-n propyl-D- glucoside Thefollowing enumerated steps are -used to prepare this glucoside.

1. Procedure 3 applied to produce -sodium starchate.

2'. Procedure 4 applied with ethyl bromide to produce G-ethyl starchate.

3. Procedure 1 applied to produce 2-sodlum, l-ethyl starchate.

"4.' Procedure 4 applied with methyl iodide to produce 2methyl, -ethylstarchate.

5. Procedure 5 applied with n-propanol to produce 2-methyl, 6ethylanpropyl-D-glucoside.

EXAMPLE X The following enumerated steps are used to prepare thisglucoside.

1. Procedure 1 applied to produce 2-sodium starchate.

2. Procedure 4 applied wit-hmethyl iodide to produce 2-methyl starchate.

- 3. Procedure 2 applied to produce Z-methyl, 3-sodium starchate.

4. Procedure 4 applied with ethyl bromide to produce 2-rnethyl, 3-ethylstarchate.

5. Procedure 5 applied with n-propanol to produce 2methyl, 3-ethyl, a-npropyl-D-glucoside.

EXAMPLE XI Synthesis of Z-methyl, 3-benzyl, 6npropyl-aphenyZ-D-glncoside EXAMPLE X-II Synthesis of Z-ethyl, 3-methyl,6-isopropyl-abenzyl-D-glncoside The following enumerated steps are usedto prepare this glucoside.

l. Procedure 1 applied to produce 2-sodium starchate.

,2. Procedure 4 applied with ethyl bromide to produce Z-ethyl starchate.

3. Procedure 2 applied to produce Z-ethyl, 3- sodium starchate.

30 4. Procedure 4 applied with methyl iodide to produce 2ethyl, 3-methylstarchate.

5. Procedure 3 applied to produceZ-ethyl, 3-

methyl, 6sodium starchate.

6. Procedure 4 applied with isopropyl bromide to produce 2-ethyl,3-methyl, -isopropyl starchate.

7. Procedure 5 applied with benzyl alcohol to produce 2ethyl, B-methyl,6-isopropyl-a-benzyl- D-glucoside.

EXAMPLE'XHI Synthesis of Z-methyl-D-glucose The following enumeratedsteps are used to prepare this glucose derivative. i

1. Procedure 1 applied to produce 2-sodium starchate.

2. Procedure 4 applied with methyl iodide to produce 2-methyl starchate.

3. Procedure 6 applied to produce 2-methyl-D- glucose.

EXAMPLE XIV Synthesis of -methyl-D-glucose The following enumeratedsteps are used to prepare this glucose derivative.

l. Procedure 3 applied to produce -sodium starchate.

2. Procedure 4 applied with methyl iodide to produce -methyl starchate.

3. Procedure 6 applied to produce -methyl-D- glucose.

EXAMPLE Xv Synthesis 0f 2,3-dimethyl-D-glucose The following enumeratedsteps are used to prepare this glucose derivative.

1. Procedure 2 applied to produce 2,3-disodiuml starchate.

2. Procedure 4 applied with methyl iodide to produce 2,3-dimethylstarchate.

3. Procedure 6 applied to produce 2,3-dimethyl- D-glucose.

EXAMPLE XVI Synthesis of 2,6-dimethyZ-D-glucose The following enumeratedsteps may be used to prepare this glucose derivative.

1. Procedure 3 applied to prepare 6sodiurn starchate.

2. Procedure 4 applied with methyl iodide to produce 6methy1 starchate.

3. Procedure l applied to prepare Z-sodium, 6- methyl starchate.

4. Procedure 4 applied with methyl iodide to prepare 2,6-dimethylstarchate.

5. Procedure 6 applied to produce 2,6-dimethyl- D-glucose.

EXAMPLE XVII Synthesis of 2-methyl, 3-ethyl, 4-butyl,-benzyla-methyl-D-glucoside The following enumerated steps are used to'.

prepare this glucoside.

l. Procedure 1 applied to produce 2-sodium starchate.

2. Procedure 4 applied with methyl iodide to produce Z-methyl starchate.

3. Procedure 2 applied to produce 2-methyl, 3- sodium starchate.

4. Procedure 4 applied with ethyl bromide to produce Z-methyl, S-ethylstarchate.

5. Procedure '7 applied with benzyl chloride to produce 2methyl,3-ethyl, 6-benzyl starchate.

6. Procedure 5 applied with methanol to pro-

1. A PROCESS OF PRODUCING A GLUCOSIDE WHICH COMPRISES THE STEPS OFREACTING STARCH WITH AN ALKALI METAL HYDROXIDE SELECTED FROM THE CLASSCONSISTING OF LITHIUM HYDROXIDE, SODIUM HYDROXIDE, AND POTASSIUMHYDROXIDE DISSOLVED IN AN ALCOHOLIC SOLVENT, AT A TEMPERATURE OF FROM78* C. TO APPROXIMATELY 115* C. WITH THE ALKALI HYDROXIDE PRESENT IN ATLEAST APPROXIMATELY STOICHIOMETRIC QUANTITIES IN RELATION TO THE STARCHTO PRODUCE A 2-MONOALKALI STARCHATE; REACTING THE 2-MONOALKALI STARCHATESO PRODUCED WITH AN ALKALI HALIDE DISPERSED IN A NONAQUEOUS SOLUTION ATA TEMPERATURE OF FROM 80* C. TO 115* C. TO PRODUCE A 2-MONOORGANICSTARCHATE; REACTING THE 2-MONOORGANIC STARCHATE SO PRODUCED WITH ALKALIHYDROXIDE SELECTED FROM THE CLASS CONSISTING OF LITHIUM HYDROXIDE,SODIUM HYDROXIDE, AND POTASSUM HYDROXIDE DISSOLVED IN AT LEASTAPPROXIMATELY STOICHIOMETRIC QUANTITIES IN AN ALCOHOLIC SOLVENT AT ATEMPERATURE IN EXCESS OF 115* C. WITH PROVISION FOR REMOVAL OF WATERFORMED BY THE REACTION TO PRODUCE 2-MONOORGANIC, 3MONOALKALI STARCHATE;REACTING THE 2-MONOORGANIC, 3 -MONOALKALI STATCHATE WITH AN ALKYL HALIDEAT A TEMPERATURE OF AT LEAST 115* C. TO PRODUCE A 2,3-DIORGANICSTARCHATE; REACTING THE 2,3-DIORGANIC STARCHATE TO FORMED WITH AN ALKALIMETAL SELECTED FROM THE CLASS CONSISTING OF LITHIUM, SODIUM, ANDPOTASSIUM DISSOLVED IN AMMONIA WITH THE ALKALI PRESENT IN APPROXIMATELYSTOICHIOMETRIC QUANTITIES WITH THE STARCHATE TO PRODUCE A 2,3-DIORGANIC,6-MONOALKALI STARCHATE; REACTING THE DIORGANIC MONOALKALI STARCHATE SOFORMED WITH AN ALKALY HALIDE TO PRODUCE A 2,3,6-TRIORGANIC STARCHATE;MIXING THE TRIORGANIC STARCHATE SO FORMED WITH AN ALCOHOLIC ACIDSOLUTION TO PRODUCE BY GLUCOSIDE HYDROLYSIS OF THE STARCHATE A2,3,6-TRIORGANIC A-GLUCOSIDE; AND ETHERIFYING THE GLUCOSIDE SO FORMED TOPRODUCE A 2,3,4,6-TETRAORGANIC A-GLUCOSIDE.